Direct injury to the sciatic nerve and other major nerves in the peripheral nervous system (PNS) may cause chronic neuropathic pain. Multiple mechanisms are involved in the development and maintenance of neuropathic pain. These mechanisms involve neurons and glia at the site of injury, in the dorsal root ganglia, and in the spinal dorsal horn. At the injury site, diverse extracellular mediators, including cytokines and proteases, provide communication between damaged axons, Schwann cells, and preserved C-fibers, which may be very important in pain processing. We hypothesize that receptors which regulate the extracellular microenviron- ment within the injured nerve may regulate neuropathic pain. The low-density lipoprotein receptor related pro- tein-1 (LRP-1) is a multifunctional receptor that binds numerous extracellular mediators implicated in the res- ponse to PNS injury. Ligand-binding to LRP-1 results in receptor-mediated endocytosis and also in cell-signaling. We have demonstrated for the first time that Schwann cells express LRP-1 and that LRP-1 expression is increased in Schwann cells by nerve injury. LRP-1 expresses activities that may be important in nerve in- jury, including regulation of Schwann cell activation and survival, regulation of the response to inflammatory cytokines, and management of myelin debris. LRP-1 also appears to regulate spontaneous and evoked pain- related behavior. The goal of this research program is to elucidate the function of membrane-anchored LRP-1 and the shed form of the receptor in peripheral nerve injury. In Aim 1, we will apply a series of "loss of function" and "gain of function" approaches to study the activity of LRP-1 as a regulator of Schwann cell biology in vitro, in sciatic nerve injury in vivo, and in the development of neuropathic pain. In Aim 2, we will study LRP-1 ligands, which may be essential in triggering LRP-1-dependent cell-signaling pathways that regulate the res- ponse to PNS injury. Finally, in Aim 3, we will elucidate the role of LRP-1 in the clearance of myelin debris in the injured sciatic nerve. Overall, these studies will offer insight into novel mechanisms that may control the progression of peripheral nerve injury and the development and maintenance of neuropathic pain. We hope to elucidate novel pathways by which Schwann cells regulate neuropathic pain. Furthermore, these studies offer the opportunity for developing novel strategies to treat or prevent neuropathic pain.7. PUBLIC HEALTH RELEVANCE: Direct injury to nerves in the peripheral nervous system may cause chronic pain. Currently, most of the therapeutics for chronic pain treatment are not effective. This grant application seeks to understand the molecular mechanisms underlying peripheral nerve injury and with that understanding, build a foundation in which we can develop novel therapeutics for chronic pain.